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Ancel Keys and the Seven Countries Study: An Evidence-based Response to Revisionist Histories

WHITE PAPER

Commissioned by The True Health Initiative http://www.truehealthinitiative.org/

With emphasis on primary source material, historical records, and review/critique by Seven Countries

Study investigators

August 1, 2017

Pett KD1, Kahn J2, Willett WC3, Katz DL4,5

“The whole of anything is never told” Henry James

Acknowledgements: The authors and the True Health Initiative acknowledge gratefully the detailed reviews, critiques, and commentaries of the following researchers directly involved in the Seven Countries Study, and/or in related, subsequent research: Henry Blackburn, MD; Mayo Professor Emeritus University of Minnesota School of Public Health David R. Jacobs, Jr., PhD; Mayo Professor of Public Health, Division of Epidemiology and Community Health, University of Minnesota School of Public Health Martijn B. Katan, PhD; Emeritus Professor of Nutrition, VU University Amsterdam, Department of Health Sciences, the Netherlands Daan Kromhout, PhD, MPH; Professor of Diet, Lifestyle, and Healthy Aging at the University of Groningen, The Netherlands and Adjunct Professor of the University of Minnesota, Minneapolis, USA Alessandro Menotti, MD, PhD; Vice-President, Association for Cardiac Research, Rome, Italy Paolo Emilio Puddu, MD, PhD; Professor of Cardiology, Sapienza University, Rome, Italy and Professor of Physiology, University of Caen, Normandy, France Jaap C. Seidell, PhD; Distinguished Professor of Nutrition and Health and Director, Institute for Health Sciences, Vrije Universiteit and the VUA, the Netherlands

1KatherinePett,MS,MEd,RDN2JoelKahn,MD,FACC,ClinicalProfessor,WayneStateUniversitySchoolofMedicine3WalterWillett,MD,DrPH,ProfessorofEpidemiologyandNutrition,HarvardT.H.ChanSchoolofPublicHealth4DavidKatz,MD,MPHFounder & President, The True Health Initiative, Immediate Past President, The American College of Lifestyle Medicine, Director, Yale University Prevention Research Center 5Correspondingauthor:David.Katz@yale.eduwithccto:Helen.Day@yalegriffinprc.org

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… Competing Interests This work was a voluntary contribution by the authors to the True Health Initiative, and was uncompensated. The authors have no competing interests to disclose.

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Table of Contents

ABSTRACT 4

EXECUTIVESUMMARY 5

SEVENCOUNTRIES:ANOVERVIEW 9SEVENCOUNTRIES:DESIGNANDMAINOUTCOMES 11SELECTIONOFCOUNTRIES:DIETANDDIPLOMACY 13SELECTIONOFCOUNTRIES:STATISTICS 14PRIMARYFINDINGSOFTHESTUDY 17FINDINGSOFDIETANDDISEASE 17

BEGINNINGTHECONTROVERSY 20ADDRESSINGCHERRY-PICKINGACCUSATIONS:HISTORYOFTHE6-COUNTRYGRAPH 22THESIX-COUNTRYGRAPH 24YERUSHALMYANDHILLEBOE’SRESPONSE 26INFERRINGCAUSALITY 30THEEFFECTS 30THEEXCLUSIONOFFRANCE 32FRANCEWASNOTEXCLUDED 32THEFRENCHPARADOXINTHE1950S:POORRECORDSANDPOORDIAGNOSES 34THESEVENCOUNTRIESSTUDY:DIETARYDATAINGREECE 37DIETARYDIFFERENCESDURINGLENT 37THEROCKEFELLERFOUNDATIONSTUDY 40SUGARVS.SATURATEDFATINHEARTDISEASE 43MECHANISTICINVOLVEMENTINHEARTDISEASE 44AFOLLOW-UPIN1999 46

STRENGTHSANDLIMITATIONSOFTHESEVENCOUNTRIESSTUDY 48

CONCLUSIONS 51

EDITORIALEPILOGUE: 54

THELEGACYOFANCELKEYSANDTHESCS 54

REFERENCES 58

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ABSTRACT

Disparagements of the methods, intentions, and conclusions of the Seven Countries

Study are currently much in vogue. They populate books and on-line commentary, and

figure prominently in prevailing dietary trends and debates. Critics frequently point out

alleged flaws in the seminal study in order to contest its primary dietary finding, that

saturated fat was correlated with heart disease, and call into question subsequent nutrition

research. This paper was commissioned by the True Health Initiative to explore the

historical record and address the popular contentions with primary source material and

related work, and in consultation with investigators directly involved. Popular criticisms

directed at the study, and the lead investigator, Ancel Keys, turn out to be untrue when

the primary source material is examined.

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EXECUTIVE SUMMARY

The Seven Countries Study (SCS) is an observational cohort study, started in 1958, to

examine relationships among lifestyle, biomarkers, and heart disease.1–4 The study was a

massive undertaking requiring cooperation among scientists worldwide. Data collection

and analysis spanned decades and were conducted concurrently with numerous

groundbreaking epidemiological studies, including The Framingham Heart Study.5

Ultimately, SCS suggested a link between dietary intake, specifically saturated fat, and

heart disease. This conclusion, which corroborated other clinical and epidemiological

evidence at the time, generated numerous hypotheses and has since inspired countless

clinical trials.

SCS and its originator, Ancel Keys, have come under fire in recent years, particularly

since Keys’ death in 2004, and often in the context of popular nutrition narratives

claiming that prevailing nutrition science is incorrect. Frequently, these critics believe

strongly that carbohydrate, and not fat, is the source of heart disease and other illness-

and do not allow for the possibility that both macronutrient classes, or specific food

sources of them, might be involved. Though SCS itself never concluded that total fat

intake should be restricted, writers – often bloggers – contend that the work of Ancel

Keys and this study in particular are at fault for low-fat dietary trends, guidelines, and

nutrition policy. As a result, modern critiques of seminal nutrition research often use

SCS, and misperceptions around its methodology, as a focal point.

While continuing reanalysis of all science is part of the self-correcting process of the

scientific method, it is important that these criticisms be based in fact and the

documented historical record. There are, of course, limitations to SCS, which will be

addressed in this paper. However, some narratives in the form of revisionist histories

proposed to discredit SCS and Keys are untrue upon review of primary sources. Many of

these narratives have become widely accepted by means of frequent repetition,

particularly since the advent of social media. These criticisms include four primary

allegations:

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1. Countries were selected and excluded based on desired outcome.

Keys and his team are often accused of picking only countries they believed

would prove their theories and that France was purposefully excluded for this

reason.

While it is true that selection of cohorts was non-random, selection was based on

practicality and dietary variation.1–4 Allegations suggesting that SCS researchers

chose locations where they already knew the outcomes are clearly false based on

review of primary source material, the relevant timelines, and direct questioning

of investigators.

2. France was purposefully excluded

France, which had particularly poor dietary data, was not excluded from the

study.6,7 A French representative was present during the SCS pilot study in

Nicotera, Italy, but ultimately researchers from France decided not to participate. 2,3,8,9

Critics attest that France was excluded because researchers were aware of the

“French Paradox”, but this concept represents an anachronism, since the

information and associations being used today to allege bias were simply not

available at the time the SCS was being designed and implemented.10

3. Dietary data in Greece taken during Lent introduced a distortion.

Some critics believe that nutrient intake, particularly in Greece, was inaccurate

due to dietary surveys being administered during Lent.11

In fact, dietary data were purposefully collected during Lent in order to account

for important seasonal variation in intake.12 Researchers, who published average

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intake of each survey period in dietary tables, found that there were no

meaningful differences in macronutrient or total energy intake during Lent versus

other times in the two Greek cohorts. These dietary findings from Greece were

consistent with an unaffiliated dietary study completed in Crete in 1948 and

published in 1953.13,14

4. Sugar was not considered as a possible contributor to coronary heart disease.

Critics contend that SCS did not appropriately address sugar intake in the

analysis. Some also suggest that a later re-analysis of SCS data found sugar was

more strongly associated with heart disease than saturated fat.15

The 1980 SCS monograph, an in-depth analysis of 10-year findings, did examine

the association of sucrose and indeed found it to be associated with heart disease.3

However, the association disappeared when saturated fat was also added into the

statistical model, suggesting that sugar was associated with heart disease mostly

due to its strong correlation with saturated fat in the diet. In contrast, the

association between saturated fat and heart disease persisted after adjusting for

sugar, suggesting it to be the primary and more significant factor. The 1999

reanalysis, contrary to one retelling, did not find that sugar was more highly

associated with coronary heart disease than saturated fat; its findings were

consistent with earlier SCS publications.16

This paper examines each of these assertions using evidence from primary sources,

historical records, and observations from SCS investigators directly involved, and

assesses each contention in historical and scientific context.

First, the paper provides the historical context and description of the SCS: how it was

conducted, concurrent epidemiological studies, and the study findings reported through

1986. Next, the paper examines and assesses each of the most common criticisms one by

one. Conclusions regarding the popular narratives (i.e., revisionist histories) are drawn

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with direct reference to the relevant evidence. Limitations to the SCS are summarized as

well.

Finally, in an epilogue/editorial comment, the legacy of the SCS and the lifelong

work of Ancel Keys are briefly considered. What role, if any, did Ancel Keys play in the

“low fat” era of nutrition policy? What conclusions were reached by Keys regarding

saturated fat, dietary cholesterol, other dietary factors, serum cholesterol, components of

the lipid panel (e.g., LDL, HDL) and heart disease- and how do these compare with the

prevailing understanding of experts today? What is known about how Keys changed his

opinions about these matters over time, and the sources used to inform such change?

This paper does not espouse or promote any dietary advice; it is intended only to

present a historically accurate account of well-documented work and redress

misrepresentations of that work. Further, but for brief mention in the epilogue, this paper

does not address how the science and research detailed here may have been co-opted and

misinterpreted by various entities in the service of various motivations not directly

accountable to the epidemiologic data. Industry and government actions during this

period represent a complex and contentious topic beyond the scope of this White Paper.

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SEVEN COUNTRIES: AN OVERVIEW

The Seven Countries Study began in 1958 to measure dietary habits, biomarkers, and

lifestyles of 12,763 men in seven countries: the United States, Italy, Finland, Greece, the

Netherlands, Japan, and two nations of the former country of Yugoslavia (now Croatia

and Serbia). The aim was to assess connections of both lifestyle and anthropometric

measures to the risk of developing or dying from coronary heart disease.1–4,12,17 The

subjects of the research were 16 cohorts of men aged 40-59. Eleven cohorts lived in rural

villages, two cohorts were railroad workers — one based in the United States and another

in Rome, Italy — one cohort was comprised of Belgrade University faculty in Serbia, one

was comprised of workers of an agro-industrial cooperative in Zrenjanin, Serbia, and

another lived in the country town of Zutphen, the Netherlands.1–3

In 1957, preparation for SCS began with a pilot study in Nicotera, Italy, a town that

ultimately was not to be included as a cohort in the study.1,3,9 This is where researchers

developed and tested their standardized methods for recruitment and enrollment and

biomarker measurements to ensure collection would be uniform across all sites.

Researchers representing all sites were present at the pilot study. Nicotera served as a

dress rehearsal for the main study, which began in 1958.3,18

In each town, investigators enrolled eligible men and collected baseline data

including blood cholesterol, blood pressure, BMI, and electrocardiograms (ECG).2,3 They

collected participants’ medical and smoking histories, and they classified level of

physical activity based on profession. Diet records were taken in representative

subsamples of cohorts as described below.

For SCS, researchers developed new procedures to improve the accuracy and

reliability of any medical diagnoses. In previous studies that relied on national disease

and death data comparisons, differences in diagnostic criteria for heart disease accounted

for much of the variability between countries.10,19 To avoid this, the investigators

developed strict codes for categorizing diagnosis.3,20–22 All ECGs were sent to the

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University of Minnesota for analysis and classification to reduce variability in data

interpretation. The Minnesota Code was developed to reduce observer error and provide

strict guidelines so type and incidence of coronary heart disease were uniformly

categorized.

Researchers were similarly concerned with collecting consistent dietary data. In all

but the US and Italian railroad cohorts, researchers collected thorough seven-day diet

recall diaries;3,4 a representative subsample of 30-50 men was chosen from each cohort to

complete intensive seven-day weighed food records. Under dietitian supervision, all food

and drinks consumed were weighed. In addition, duplicate samples of all foods eaten

were collected, freeze dried, and sent to the University of Minnesota for chemical

analysis.4,12 Both the results from dietary recall data and weighed food sampling were

published and compared in order to validate intake measures.12,23 In the US, intake was

estimated using 24-hour recalls and food frequency questionnaires. For the Italian

railroad cohort, seven-day diet records and food frequency data were collected.4

Achieving a high follow-up rate among participants was a primary concern during

study design, and the choice of measurements was made with this in mind. Oral glucose

tolerance was suggested as part of an initial protocol, but was excluded due to expense

and concern that participants might not return if visits lasted an additional hour.3

Beginning in 1970, glucose tolerance tests were carried out in some cohorts, notably

Zutphen, Netherlands, over the remaining course of the study.18

At five and 10 years, all cohorts were revisited — except the two Japanese cohorts

were not examined at year 5 and the U.S. Railroad cohort, which was not examined at

year 10 due to lack of funding — and biomarkers and electrocardiograms were taken

again.3 New cases of heart disease were diagnosed and death records from all cohorts,

including those for the railroad workers cohort in the U.S., were carefully combed.

Deceased participants’ causes of death were examined and validated by the research

team. Publications following up on the SCS cohorts after the 10-year mark examined

coronary heart disease mortality and all cause mortality.4,16,18

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As with coronary heart diagnoses, similar care was taken in verifying official cause of

death. Death certificates for each individual, rather than official mortality statistics, were

used and in more than half of deaths, researchers corroborated cause of death by

interviewing a participant’s family, physicians, and/or obtaining hospital records. Even

when only a death certificate was available, a critical review was made to define cause of

death according to standardized criteria.18

Three book-length study analyses were published in 1966, 1970 and 1980.1–3 The 10-

year (1980) and 15-year (1986) follow-up publications are important sources for the

present paper; many other details can be found in the voluminous literature generated by

the SCS.3,4 The great number, and length, of SCS publications can prevent readers from

grasping the scope and details of the study, since each paper inevitably presents only a

small part of the whole story. Keys, and the large team of authors representing all of the

participating nations, tracked correlations, evaluated outcomes, and determined what

conclusions could be drawn from decades of evidence. SCS primarily examined the

relationship among cohorts between diet and coronary heart disease, and secondarily,

correlations within cohorts among lifestyle, biomarkers, and coronary heart disease.2–4,18

Seven Countries: Design and Main Outcomes

The Seven Countries Study is a type of observational study known as a “prospective

cohort study.” For a cohort study to examine outcomes such as coronary heart disease, it

must enroll participants who do not possess the condition at baseline and then collect data

on these participants and cohorts over time. As time goes by, researchers assess the

incidence of and mortality from a given disease within and/or across the study

populations. Researchers then track whether baseline measurements, like high blood

pressure, are associated with differing propensities for disease development and

mortality. Because researchers only observe participants and do not introduce dietary or

lifestyle interventions, this is known as an “observational” study or specifically “cohort

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study.” A cohort study that follows participants over an extended period of time can also

be referred to as “longitudinal” or “prospective.”

Perhaps the most famous study of this type is The Framingham Heart Study, which

followed select citizens of Framingham, MA, and was one of the first studies to show the

damages caused by cigarette smoking.5,24,25 To provide some historical context, The

Framingham Heart Study was merely 8 years old at the start of the Seven Countries

Study; the first major findings were published in 1957, a year before official data-

collection in SCS would begin.24

Numerous cohort studies examining relationships between lifestyle and coronary

heart disease were in their early years at the time of SCS. The Minnesota Business and

Professional Men Study, also by Keys and his Minnesota colleagues, had started in

1947.26 In a table of cohort studies predating SCS, Keys noted that on the West Coast, a

cohort study in Los Angeles civil servants started in 1950 and one in San Francisco

longshoremen started in 1951.27 In Albany, NY, similar observational studies began on

civil servants in 1953.3 Other major observational studies would continue to form

throughout the ‘50s and ‘60s and sample sizes would trend upward.3

Unlike many prospective cohort studies, which are performed in a limited

geographical area, the cohorts in SCS were ecologic units. Many of the aspects of the

SCS, including diet, were analyzed as an “ecological” study, meaning that Keys et al.

examined correlations between the mean values of data points of the 16 geographic

cohorts, as well as comparing the data from each individual.3 An ecological study looks

at the associations between exposure variables, and outcome variables, at the level of the

sub-population. A semi-ecologic study also collects and analyzes data among individuals;

thus, depending on the focus of study, SCS is an “ecologic” or a “semi-ecologic” study

(see “Strengths and Limitations,” page 48).

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Selection of Countries: Diet and Diplomacy

Running a multinational cohort study in 1956 presented a series of challenges. Only a

little more than a decade past World War II, there were diplomatic and practical concerns

for country selection. In order to participate, funding needed to be secured for each

cohort, a precluding barrier for some countries. Indeed, SCS was unable to sustain

funding for its American cohort and so disease incidence of the US cohort, assessed by

ECG and clinical examination, was dropped as an outcome after the five-year follow-

up.1,3

Competency and familiarity with each region were other considerations. The

University of Minnesota team attempted to work with researchers and in regions with

which their international colleagues had knowledge and contacts, and where they were

welcome.3 Cooperation from village leaders and citizens was essential for adequate

follow-up, which required the presence of scientists native to each of the included

countries. Keys and his team benefitted from existing international contacts that assisted

in scouting and suggesting locations. Many of the small communities chosen had

participation rates of greater than 90%, an impressive feat requiring substantial local buy-

in. The lowest participation rate for coronary heart disease incidence, still comparatively

high among observational studies, was among the American railroad workers who were

concerned that their jobs would be at stake if researchers discovered poor health.3

Follow-up for total mortality was near 100% for the first 15 years.18 Follow-up for vital

status and cause of death was nearly complete for most cohorts for 25 years, and for

select cohorts, for 50 years.

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Selection of Countries: Statistics

Researchers carefully selected populations across a wide variation of dietary patterns,

but with low variance of other characteristics to limit confounding. The rural cohorts in

SCS were identical in age distribution and gender, and highly similar in level of

education, socioeconomic status, and laborer lifestyle, but not in diet.1–4 This ideally

reduced confounding when comparing cohort means, while maximizing variability in

cohort diets and coronary heart disease incidence.

At the time of SCS, all epidemiological studies examining health outcomes in relation

to diet in single populations encountered a nearly insurmountable practical and statistical

problem. The day-to-day variation in the diet of a single individual (called intra-

individual variation) was of nearly the same magnitude as variation in diet between

individuals (inter-individual) of the same culture.3,28–30 In order to be reasonably

confident of a difference between one person’s diet and his neighbors’, dietary surveys

would need to have been repeated upwards of seven times.3 This approach was

impractical, prohibitively expensive and, even then, unlikely to discover major

differences among individuals eating a relatively homogenous diet without a much larger

sample size.

For these reasons, Keys thought it was imperative to compare disease rates where the

average diets of populations varied over a wide range in order to see possible

relationships between nutrient intake and chronic disease risk.1–3,18 Consider that in a

population where everyone smokes, it would be nearly impossible to find smoking

associated with increased risk of lung and mouth cancers, even though true. A

measurable difference in outcomes requires a discernible difference in exposure.

Hence, the choice of populations with divergent dietary patterns was crucial to the

early study of possible causes of heart attack. Historically, much of the initial information

that suggests diet’s impact on health has come from observations of populations with

outlying diets and disease incidence, including the classic observations in China and Java,

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Seventh Day Adventists in Loma Linda, and smaller but more recent observations among

the Maasai in Kenya and northern Tanzania, and most recently among the Tsimané of

Bolivia.31–34

Of the seven countries, the United States and the Netherlands each provided a single

cohort, the former Yugoslavia (now Croatia and Serbia) provided five, Italy three, and

Japan, Greece, and Finland each contributed two.1–4 In most cases, cohorts within each

country were selected because of purported differences in eating habits, thus potentially

providing dietary variation between a region’s cohorts. In the analysis, comparisons were

therefore made between individual cohorts as well as between countries.

The United States was an obvious choice because the research team was based in

Minnesota.3 Researchers and public health officials were interested in discovering factors

linked to the relatively high incidence of coronary heart disease plaguing middle-aged

men in the U.S.

Japan had an extremely low rate of reported coronary heart disease and a national diet

uniquely low in fat, though it was unclear whether particular health outcomes reported

were due to diet, the Japanese tendency to record sudden deaths as cerebrovascular, or

both.1 The Japanese cohort in Tanushimaru was a farming community, while the

Ushibuka cohort was a fishing community with a diet higher in seafood.18

North Karelia, Finland, was known for high-fat diets and allegedly had extremely

high rates of coronary heart disease. The West Finland cohort included men in two rural

villages, where coronary heart disease was purportedly lower than in East Finland.18

The Greece cohorts in Crete and Corfu were included because they reported low

mortality from coronary heart disease, but high intakes of fat, particularly olive oil.3,18

Sites in Croatia (former Yugoslavia) were chosen with help from a native colleague,

Ratko Buzina, who provided staff for data collection in these regions.3 This allowed

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researchers to minimize costs and achieve high survey response rates. Interestingly, the

five sites in former Yugoslavia were characterized by supposedly different dietary

patterns. The Dalmatia cohort was known for a high vegetable Mediterranean-style diet,

the Slavonia cohort had a more traditional central European diet high in animal

products.18,35 The three Serbian cohorts were chosen based on varying socioeconomic

status and reportedly had similar diets; Zrenjanin included men working on an

agricultural cooperative; Belgrade, the faculty at the University of Belgrade; and Velika

Krsna, farmers in the rural village south of Belgrade.18,35

The rural regions of Italy were chosen for similar reasons: varied diets between

cohorts. The Rome railroad workers provided the “Italian counterpart” to the U.S.

railroad cohort. Crevalcore, in northern Italy, purportedly had a diet higher in animal fat

while Montegiorgio had a diet more traditionally “Mediterranean.”18 The Netherlands

was included because the Dutch government nutritionists were collegial and curious to

join the pioneering comparisons among cultures.3,36

Notably, Keys and his team wanted to include areas with differing rates of coronary

heart disease, but relied on uncertain estimates by local experts of the prevalence of

disease, since government reported death rates at the time were unreliable indicators.7

Much of the modern criticism of the SCS is aimed at the selection or non-selection of

various regions, a topic that will be covered in a later section (page 22). It’s important to

note that country selections aimed to include a wide range of diets so that a statistical

effect could be measured if it existed. Selection was also shaped by the practical

considerations of cost and connections imposed on carrying out research in any capacity.

Additionally, other than preferential addition of developed nations with very diverse diets

to improve the power of the study, lack of interest, preparation, or funding were the only

reasons for excluding countries. Countries with willing researchers and ready funds were

welcome.8

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This paper focuses primarily on the findings reported in the 1980 and 1986

publications, which evaluated 10- and 15-year coronary heart disease incidence and

mortality, as well as all-cause mortality.3,4

Primary Findings of the Study

Deaths from coronary heart disease were consistent with the data coming from

scattered sources before the study commenced.3 Northern Europe and America

experienced a much higher incidence of and mortality rate from coronary heart disease

than did men of the same age in Southern and Central Europe. Japan was characterized

by very low reported coronary heart disease death rates.3

The finding most debated today was that the average cohort intake of saturated fat (as

percent of calories or energy) was statistically significantly associated with cohort rates

for coronary heart disease3. Total dietary fat was not associated with coronary heart

disease. For example, the Greek cohorts ate about 40% of their daily calories from fat and

the Japanese ate only 10% while both cohorts had very low coronary disease rates.3,4 SCS

was the first systematic study to illustrate this important dichotomy, that low rates of

coronary heart disease and, in fact, of total mortality can be found with low and high total

fat intakes, depending on the nature/sources of the fat and the rest of the eating pattern.3

Findings of Diet and Disease

Keys et al. assessed associations among cohorts using a multivariable linear

regression.3 This method was to evaluate potential ecological correlations between

lifestyle and disease while controlling for potential confounding factors. Simple

correlations can be found by comparing two measurements, but don’t allow researchers

to conclude that the correlation is specific to the dependent and independent variables

examined. This is because there are other circumstances possibly associated with both

major variables that are not accounted for in a simple correlation; these are known as

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confounders. Adjusting for confounders does not allow researchers to overcome the

primary limitation of observational studies and determine causal relationships, but can

increase confidence that a correlation is valid and meaningful.37

A multivariable regression accounts for confounding factors by controlling for them

within the statistical analysis. With this method, researchers can assess the effect of the

exposure (such as a diet) on the outcome (such as coronary heart disease) including

possible confounders in the equation. By including multiple factors possibly associated

with coronary heart disease including weight, blood pressure, physical activity, and diet,

researchers could more reliably distinguish between true correlation and coincidence. Of

note, however, is that such adjustment is never perfect, and particularly in an ecological

analysis does not serve to establish cause-and-effect.

Keys et al. measured the ecologic association between saturated fat and coronary

heart disease controlling for total caloric intake3. Sugar was included in the model, which

assessed the effect of saturated fat intake when adjusted for sugar intake. Saturated fat

remained statistically significantly associated with heart disease in that model. The

opposite circumstance did not hold true. When sugar was the independent variable,

adjusting for saturated fat intake eliminated any observable association between sugar

consumption and the incidence or mortality from coronary heart disease.3,38 In other

words, the analysis suggested that any variation in heart disease concurrent with sugar

intake was “explained away” by variation in saturated fat intake, whereas variation in

heart disease concurrent with variable saturated fat intake was not explained away by

variation in sugar intake. Saturated fat emerged directly from the data analysis as the

predictor variable of singular apparent importance.3,4

There are numerous claims, mainly on blogs, attesting that SCS did not include sugar

in its statistical models; this is not the case.3,38 However, high intake of refined

carbohydrates is now considered to be a possible contributor to heart disease

development;39,40 this was not evaluated. In SCS, saturated fat intake was correlated with

sugar intake and cohorts with diets higher in saturated fat also consumed more sugar.3

19

Tellingly, saturated fat intake was non-significant when serum (not dietary)

cholesterol was added into the statistical model as a control variable.3 Earlier

experimental studies had clearly demonstrated that saturated fat intake caused increased

serum blood cholesterol when substituted for carbohydrate or compared to

supplementation with mono or polyunsaturated fatty acids.41,42 The significant

relationship between saturated fat intake and heart disease was eliminated when adjusted

for serum cholesterol, which suggested that serum (not dietary) cholesterol was a key

mediator.3 To summarize: Keys et al.’s findings suggested that the correlation between

saturated fat and increased coronary heart disease was due to the correlation between

saturated fat intake and higher serum cholesterol levels, which subsequently affect

coronary heart disease risk. Sugar was analyzed in exactly the same way as saturated fat,

but did not demonstrate a significant association with relevant outcomes independently.3

Findings from the 1986 evaluation of coronary heart disease and all-cause mortality

were consistent with those of the 1980 monograph.3,4 Further, Keys et al. found that

saturated fat intake, specifically the ratio of saturated to monounsaturated fatty acids, was

significantly associated with death from coronary heart disease as well as all-cause

mortality.3,4

Though high serum cholesterol was significantly associated with coronary heart

disease outcomes, at the time of the analysis in 1980, Keys et al. concluded that there was

likely a threshold under which average population cholesterol level might not be

associated with increased risk.3 Later evidence with huge samples found individual

coronary heart disease risk continuous with serum cholesterol, particularly LDL, from

low to high.43

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BEGINNING THE CONTROVERSY

The SCS was one of many longitudinal observational studies in the mid 20th century

that attempted to discover why coronary heart disease mortality in the United States and

Northern Europe seemed high. Unlike most of those concurrent studies, Keys et al. used

an ecological approach to compare the lifestyles and risk factors among entire

populations and diverse regions across a wide variety of traditional eating patterns.

Why has the study become controversial? Over time, numerous arguments emerged

asserting that Keys’ seminal study was wrong, or worse, that data were altered or selected

to reflect specific outcomes. It is possible that modern critiques of a study that began over

60 years ago led to careless handling of historical facts.

The SCS, like all scientific endeavors, was not without limitations, which will be

summarized below. But attempts to paint the study as “corrupt” or “cherry-picked” lack

merit.

To demonstrate this, we critically examine claims frequently made including:

1. That Keys, et al. selected countries with a specific outcome in mind; that SCS

had data from 22 countries but highlighted only seven.

2. France was deliberately excluded because the SCS research team was aware of

the “French Paradox.”

3. That dietary surveys made in Greece were invalid because they occurred

during Lent.

3. That an analysis of SCS data published in 1999 proved that sugar, and not

saturated fat, was associated with coronary heart disease.

Authors referred to primary literature as well as communication with original

members of the SCS research team to evaluate claims that have become popular on blogs

and in diet books. The authors note that this effort illustrates “Brandolini’s Law:”

21

“The amount of energy needed to refute [misinformation] is an order of magnitude bigger than to produce it.”44

22

Addressing Cherry-picking Accusations: History of the 6-Country Graph

Many critiques start with a cherry-picking argument: Keys had data from 22 countries

and chose only the seven that fit his hypothesis.45 This accusation is startlingly pervasive,

yet demonstrably false.

Where does this argument come from? Misrepresentations of the source of the data

are years old; Keys himself responded to critics who incorrectly thought SCS data came

from national statistics.46 Speakers, bloggers, journalists, and other detractors of SCS

frequently cite this graph:47

Figure 1: From "Atherosclerosis: A problem in newer public health," Journal of the Mount Sinai Hospital, 1953. This image has been reproduced from widely available reproductions accessible online. Permission to reproduce the original has been sought from the publisher, and a response is pending at this time.

And then this one:6

23

Figure 2: From "Fat in the diet and mortality from heart disease: A methodologic note," 1957, New York State Journal of Medicine. Permission to reprint granted by the publisher.

The first graph is from a paper by Ancel Keys, showing a correlation between fat in

the diet, calculated from national disappearance data, and World Health Organization

(WHO) data on heart disease in six countries.47 The second, from a paper by statisticians

Jacob Yerushalmy and Herman Hilleboe, shows the same relationship but with 22

countries.6 Many critics suggest that the second graph eliminates the correlation between

fat intake and heart disease. Though it is easy to see that the positive correlation between

fat intake and heart disease remains in this version, it does appear weaker.

24

The seemingly stark contrast of these graphs side-by-side has become an enduring

argument for the inaccuracy of, and alleged “cherry-picking” of countries for — the SCS.

But neither of these graphs is from the SCS.

The first graph of six nations is from an earlier paper by Ancel Keys in 1953, more

than a decade before the first publications from SCS.47 The second is from a paper

published in 1957, nearly a year before baseline data collection began in SCS cohorts.6

Clearly, neither of these graphs uses the same data as the SCS.

The first graph is often mistakenly attributed to SCS, and critics of the study are not

fastidious about correcting the mistake. The incorrect assertion that SCS started with 22

nations and pared down to the seven that fit Keys’ hypothesis even made it to the

Wikipedia entry for SCS for a time.45 A cursory examination of the primary source

material reveals it to be a false proposition.

Legitimate confusion on the topic is likely due to the passage of time and failure to

review the full historical record. The historical context behind the development of each

graph readily clears up the controversy surrounding this mistaken assertion.

The six-country graph

In 1953, Ancel Keys’ presentation at a symposium, “Recent Advances in Therapy,” at

Mt. Sinai Hospital included the first graph displaying six countries.47 This presentation

was then published as a paper the same year, titled, “Atherosclerosis, a problem in newer

public health.”47 In it, Keys presented a wide-ranging review of the evidence available at

that time, suggesting that atherosclerosis was not simply a natural consequence of aging

and that diet might be related to heart disease outcomes. What was revolutionary about

this was the idea that heart disease could be preventable. This was an intuition Keys

could not prove at the time, though his future work and that of many others, have proven

him right.39,40,47,48

25

In the paper, Keys pointed out that diagnosis of cardiovascular disease, which he

referred to as “degenerative diseases of the heart,” varied greatly but seemed to share

common biological pathways.47 His second point was to show that serum cholesterol

tended to be higher in people with heart disease than in people without it. And thirdly, he

reviewed previous experimental evidence in humans showing that altering the amounts of

fat and dietary cholesterol in the diet affected serum cholesterol levels.47

This, along with the six-country graph, was meant to posit the following thought

process. The mortality for middle-aged men in the United States was higher than in

similarly developed countries; this mortality difference seemed to be due to higher

mortality from coronary heart disease. A higher fat intake was associated with a greater

incidence of heart disease in some countries. His conclusion was to suggest that fat intake

was correlated with coronary heart disease through serum cholesterol level, but that type

of fat might also matter.47

Keys said at the time: “Whether or not cholesterol, etc., are involved, it must be

concluded that dietary fat is somehow associated with cardiac disease mortality, at least

in middle age.” It is interesting to note that at this time, in 1953, Keys primarily posits

that change in risk may be attributable to total fat, rather than saturated fat, in the diet.47

He would later refine his thinking on this topic with data from his own work in human

cross-over dietary experiments, clinical trials, and in SCS, where only saturated fat

proved to be associated with an increase in risk.3,4,41,42 This, according to Keys’ many co-

investigators, was his consistent pattern; he would methodically test the hypotheses he

formed on the basis of provisional data, and evolve his thinking in accord with the data

and findings.49

The six-country graph appeared in a research paper that ran more than 20 pages and

included tables and results from numerous comparative studies showing the differences

in mortality, coronary heart disease mortality, and food disappearance data among

multiple countries, results of experimental data on diet and serum cholesterol, and

observational comparisons of average serum cholesterol in populations with and without

26

heart disease.47 None of this was decisive proof of cause-and-effect, but was the start of a

line of research still yielding new insights, and the basis for Keys’ hypotheses at the time.

Why did Keys choose only six countries for the particular graph? According to Keys,

these six countries represented those that had the most reliable dietary and vital statistics

at the time, in 1952.47 A consistent principle in the Laboratory of Physiological Hygiene

(Keys’ Department at the University of Minnesota) at the time and for many years later

was: the data you talk about have to be of the highest caliber, valid, reliable, and most

relevant to the scientific question.50 Additionally, numerous scientists had noticed that

WWII had changed not just total mortality statistics, but coronary heart disease death

rates as well, and that countries occupied by Germany during the war experienced

significant upheavals to traditional diets that altered their risk factors for heart disease.

“In Norway,” Keys pointed out, “the public health and vital statistics records were well

maintained and it is clear that not long after the national dietary change began, there was

a marked decline in mortality from circulatory disease, particularly arteriosclerotic heart

disease.”47

Though the paper was published in 1953, the data used by Keys in the graph (and

likely the most recent data available) were from 1949, only four years after the end of the

war. Dietary changes in Germany and the countries it occupied lasted longer than the end

of the war and could possibly have introduced bias into a simple correlation.51 In a later

paper, Keys noted “the prolonged influence of the war and its aftermath on the diets of

many countries cannot be ignored.”7,52,53

Yerushalmy and Hilleboe’s response

In 1955, Keys presented to atherosclerosis experts in Geneva the same information, in

a talk that was published as “The relationship of the diet to the development of

atherosclerosis in man.”6,54 Two public health professionals, Jacob Yerushalmy and

Herman Hilleboe, were in attendance. They were not impressed by what they interpreted

as Keys’ confidence that dietary fat was causally linked to heart disease; they felt there

27

was not substantial evidence to make a causal claim.6 Yerushalmy and Hilleboe chided

Keys for altering his “cautiously observed” correlation in 1953 to the more strident

assertion he made in 1955:

“The analysis of international vital statistics shows a striking feature when the national food consumption statistics are studied in parallel. Then it appears that for men aged forty to sixty or seventy, that is, at the ages when the fatal results of atherosclerosis are most prominent, there is a remarkable relationship between the death rate from degenerative heart disease and the proportion of fat calories in the natural diet. A regular progression exists from Japan through Italy, Sweden, England and Wales, Canada and Australia to the United States. No other variable in the mode of life besides the fat calories in the diet is known which shows anything like such a consistent relationship to the mortality rate from coronary or degenerative heart disease.”6

Yerushalmy and Hilleboe, concerned that Keys was overstating a simple correlation,

decided to investigate these claims.

Four years after Keys’ initial paper was published, Yerushalmy and Hilleboe

published a critique in July of 1957, featuring a 22-country graph showing Keys’

correlation substantially weakened.6 In September of 1957, Hilleboe published another

19-page paper focused on the same topic covering similar points.55 Of the 15 tables and

graphs included in Keys’ 1953 paper, which relied on a thorough history of clinical,

experimental, and observational evidence, Yerushalmy and Hilleboe’s July 1957 paper

chose to focus on a single piece of evidence, the six-country graph.6

They took issue with Keys’ selection of countries, since they noted that data on

dietary intake and heart disease mortality existed for 22 countries.6 Yerushalmy and

Hilleboe, however, failed to consider that food intake and heart disease incidence were

probably influenced by the war and Nazi occupation. In fact, numerous countries

included in their graph — Germany, Norway, the Netherlands, France, Denmark, and

Greece — experienced atypical food availability and intake in the years prior to and

directly after the war, the effects of which had been mentioned in Keys’ 1953 paper.7,47,51

28

Yerushalmy and Hilleboe’s criticisms of Keys’ 6-country correlation graphic were to

some extent valid, though the graph represented only a fraction of Keys’ larger

argument.6 First, they pointed out that any simple correlation by itself could not prove a

causal link between an exposure and an outcome, thus introducing the criteria for causal

inference from correlations. In fact, Keys had not claimed causation.47

Next, they questioned the quality and accuracy of heart disease diagnoses among

countries. Some countries were more precise with their diagnoses of heart disease, while

other countries were more likely to file deaths under a broader category of heart-related

deaths.6 These imprecisely categorized deaths were not included in Keys’ initial 1953

six-country assessment, and Yerushalmy and Hilleboe criticized the omission, though it’s

possible Keys considered quality of diagnosis in his selection of the six countries with

“fully comparable dietary and vital statistics.”47 Further, Yerushalmy and Hilleboe had

found another dietary factor more significantly associated with heart disease than fat:

animal protein.6

They took care to point out that their observation shouldn’t suggest animal protein

was truly correlated with increased heart disease since an “apparent association often

proves to be the result of non-pertinent extraneous factors.”6 They intended only to point

out that multiple dietary correlations could be made and that scientists can’t rely on single

associations to assume cause. In fairness, neither of Keys’ previous papers had relied on a

single correlation; they included the results of multiple observational and experimental

studies.47 Nor was causality asserted; Keys simply hypothesized in accord with the

findings, and these hypotheses, in part, were the basis for the SCS.

While Yerushalmy and Hilleboe accurately pointed out the liability of inferring

causation from correlation, their paper was not without major flaws of its own. After the

papers published in July and September of 1957, Keys responded with an editorial in the

Journal of Chronic Disease that November.7

29

According to Keys, Yerushalmy and Hilleboe had used dietary and health data

irrespective of quality; this is something Keys felt could affect results. Secondly, Keys

pointed out that in some of the included countries, dietary data could not possibly reflect

coronary heart disease data because some countries’ populations included had a large

percentage of recent immigrants whose diets were affected by their culture and country of

origin. The dietary data, then, were not reflective of the population being measured and,

thus, could not accurately be correlated with disease incidence.7

Most importantly, Keys pointed out that Yerushalmy and Hilleboe suffered from a

chronological problem – something that would later be codified in the Bradford Hill

criteria.7,56 In his September 1957 paper, Hilleboe used dietary data primarily from 1954

to analyze the relationship with earlier coronary mortality data from 1950-52.55

Keys points out that the foundations of coronary heart disease start years before

disease mortality. It is more likely that a country’s average diet in the mid- to late 1940s

would show an accurate correlation with heart disease deaths in the 1950s than would

concurrent dietary data, and implausible that a country’s average diet after recorded

disease mortality could be a true correlation, particularly if dietary patterns had changed

over time.7

It is also important to note that dietary data of the mid-1950s were not reflective of

dietary data a decade previously in many of these European countries that were gravely

affected by World War II.7 Keys points out that this is particularly the case with the

Netherlands:

“In the data as tabulated by Dr. Hilleboe and Dr. Yerushalmy, the most striking

departure from a good correlation between dietary fat in 1954 and mortality in 1950-

1952 is the case of the Netherlands… There are no reliable records for the war years, but

it is known that food fats available in the Netherlands were greatly reduced from 1940-

1944, that the diet was at the near starvation level… In no case is it proper to suggest

that the deaths in 1950-1952 should reflect the diet of the surviving population in later

30

years.”7 This comment by Keys was in direct response to a related paper published singly

by Hilleboe.55

Inferring causality

Those well-versed in epidemiology will recognize the applicability of Bradford Hill’s

criteria governing the inference of causation from correlation, but it is important to point

out that these criteria, taken for granted today, were not published until the mid 1960s.56

That is over a decade after this debate on saturated fat, and indeed after the Surgeon

General’s Report on Smoking (1964) that largely relied on epidemiological evidence to

infer causation between smoking and lung cancer.57 The academic debates on how

epidemiology should be used to influence public health policy, so eloquently summarized

in the Bradford Hill criteria, had their genesis in debates that took place in the 1950s,

including this one between Keys, and Yerushalmy and Hilleboe.58

The effects

Yerushalmy and Hilleboe, intentionally or otherwise, distorted Keys’ original point

by citing a single piece of data and critiquing it as if it were the basis for his entire line of

reasoning. However, in doing so, they made several good — if pedantic — points about

the limitations of observational evidence for inferring causal relationships.6,55

By the time Yerushalmy and Hilleboe’s paper was published, SCS was already

underway incorporating procedures designed to avoid the exact traps Yerushalmy and

Hilleboe highlighted.3 SCS would standardize the way diet and heart disease were

measured in cohorts. Rigid protocols eliminated much of the variability in local

infrastructure and diagnosis. In-depth surveys and chemical analysis of food samples

increased the exactitude of dietary data compared to relying on a country’s food

availability data. SCS would also tailor methodology to control for what Yerushalmy and

Hilleboe called the “non-pertinent extraneous factors” that create false correlations.3,6

The SCS team selected locations that allowed entire towns to be sampled and enrolled

31

mostly men of the same age and socioeconomic status, which ensured that sampled

populations would be largely similar except with regard to diet and lifestyle, the

independent variables of interest. The study’s prospective design allowed it to enroll

subjects before disease began and carefully tracked the representative diet of each cohort;

giving it a great deal more validity than using national or FAO statistics.3

In conclusion, the famous six-country graph had nothing to do with the Seven

Countries Study and was produced from an earlier analysis that used unrelated and less

robust data. Further, the epidemiological debate between Ancel Keys and Yerushalmy

and Hilleboe concerned issues about the specificity of correlations, which were controlled

for in the later and more precise and extensive data obtained in the SCS. The

presentation of graphs of 6 and 22 countries, juxtaposed to claim cherry-picking in the

SCS, is a popular falsehood; the graphs were not produced in the same study, and

NEITHER was from the Seven Countries Study.3,6,47

32

The Exclusion of France

Another popular criticism, similar to the first, is that Keys excluded countries that

didn’t fit his hypothesis. Namely, France was purportedly excluded due to the “French

Paradox.”

The “French Paradox” rests on the assumption that people in France tend to eat a diet

higher in saturated fat than people in other developed nations, yet experience lower rates

of heart disease.10 Critics believe that Keys was aware of this paradox and intentionally

left France out of the SCS. This, like the cherry-picking accusation, is demonstrably

incorrect.

France was not excluded

Missed by most revisionists is the fact that France was indeed invited to participate

in the Seven Countries Study. As previously mentioned, the SCS team wanted local

scientists from included countries to lead the project in their respective regions.3

Countries with willing, capable researchers, interest, and funds were welcome to join.

Some countries opted out due to lack of interest or resources; Sweden and Spain declined

for these reasons, respectively.8

Representatives from France had been included and Dr. Jacques Carlotti, a physician

from Paris, was part of the pilot study team in Nicotera, Italy.1,3,9 Ultimately,

representatives from France decided not to participate, possibly due to lack of desire, lack

of funding, or both. There was no explicit intent on the part of the American SCS

researchers to include or exclude France.

The “French Paradox” did not yet exist

The first reference to the now ubiquitous “French Paradox” in the literature was in

1981, making the concept a modern one. Pierre Ducimetière pointed out that the term was

33

first used in a paper by French epidemiologist J. L. Richard describing heart disease

incidence in French policemen.10 While it may have been noted that the French had rich

diets, it was not until the major diet cohort studies like Framingham and SCS were

published that the concept of France as a heart disease exception took hold.10 In fact, the

data available in the early and mid 1950s about the French diet did not suggest that

people of France had either an atypical diet or heart disease profile.6 Quite simply, even if

Keys and colleagues had been inclined to act on bias, there would have been no basis at

the time for a bias against the participation of France. All evidence regarding the SCS

suggests very much the contrary regarding Keys and colleagues, that they took pains and

went to great lengths to avoid bias in their methods.

The lack of French diet data

France was one of the many European countries occupied by Germany during World

War II, and thus experienced an extended period of dietary deprivation.7,51,53 As in much

of Europe, staple foods including animal foods and dairy were rationed and supplies

decreased throughout the war, in both Vichy and occupied France. Rationing was stopped

only in 1949 as France — like much of occupied Europe — struggled to recover after the

war’s end.51,52,59 Perhaps unsurprisingly, the food availability data for France in the late

1940s and early 1950s was not of the highest quality.

In fact, the Yerushalmy and Hilleboe paper of July 1957 inadvertently provides

evidence that international data for food availability and consumption in France were

poor.6 Of all 22 countries with varying qualities of dietary data, only France had no

available estimates for fats derived from animal and vegetable sources (proxies for

saturated and unsaturated fats).

The study record therefore belies the claim that Keys purposefully excluded France

from SCS due to concerns that France’s high saturated fat intake and low heart disease

rate would upset his hypothesis. There was little reliable dietary information available,

and none to foster any such inference. Further, the study’s design specifically included

34

countries with high fat intake and unknown levels of heart disease, such as Greece, in

order to test the relationship between total fat intake and coronary heart disease.3

Ultimately, SCS concluded that there was no observed relationship between the two; only

saturated fat showed a strong correlation.3

The French Paradox in the 1950s: Poor records and poor diagnoses

The scant evidence available in the early 1950s during the planning phase of SCS did

not show a French Paradox.

For example, see the 22-country chart from Yerushalmy and Hilleboe’s 1957 paper6

(page 23, page 35). France is represented by #8 on the chart. France does appear to have

extremely low heart disease rates, but it is also listed as having a total fat intake of less

than 30% of calories, an intake consistent with the often maligned initial dietary

guidelines of the United States.6 Few people who point to France to advocate the safety

of diets high in saturated fat encourage total fat intake this low.

Additionally, Yerushalmy and Hilleboe’s paper argued that the appearance of low

coronary heart disease mortality in France was a façade; due more to different diagnostic

criteria than to a truly lower mortality rate from heart disease.6 And so again, critics of

Keys from a half-century ago wind up refuting a popular claim among critics today.

In Keys’ 1953 review paper, he compared the dietary data of six countries using

mortality statistics from WHO Annual Epidemiological and Vital Statistics category “B-

26: Arteriosclerotic and degenerative heart disease.”6,47 Mortality from heart disease was

categorized as deaths per 100,000 people. In France, there were only 102 such deaths

ascribed to code B-26 from the 1951-1953 data, much lower than the United States’

number of 739. But Yerushalmy and Hilleboe point out that there is also the catch-all

heart disease category of “B-27: Other diseases of the heart.” In the United States, only

35 deaths per 100,000 were assigned to this category, while France had 180 per 100,000.6

If one were to combine deaths in France from B-26 and B-27, France would still have a

35

somewhat lower heart disease rate than the United States, but not impressively so, and by

no means “paradoxical.”

Below is the chart of 22 countries with France added back showing total deaths from

B-26 and B-27 included. The adjusted number is represented by the red dot.

Figure 3: Adapted from "Fat in the diet and mortality from heart disease: A methodologic note," 1957, New York State Journal of Medicine. Permission to reprint granted by the publisher.

If the deaths categorized as “B-27: Other diseases of the heart” are included in the

coronary heart disease mortality data, it is clear that France falls into line with an upward

slope demonstrating a correlation between fat intake and heart disease. Indeed, later

research has also brought to light the fact that inter-country variability in nationally

reported mortality data is a major weakness in ecological studies and may be responsible

for part of what we now think of as “The French Paradox.”10,19 Later epidemiological

36

studies on coronary heart disease across Europe showed that heart disease risk in France

is consistent with the geographic gradient seen in SCS that showed lower incidence in

southernmost regions and higher incidence moving north.60,61 Clear evidence describing

lower rates of coronary heart disease, but not all-cause mortality, in French men

disproportionate to what would be predicted based on traditional risk factors were not

defined until the 1980’s.62,63

SCS would go on to control for variability in cause-of-death diagnoses by using

study-specific researchers and standard and objective criteria to categorize and determine

official cause of death for the study data across all participating sites.3

In conclusion, the argument that The Seven Countries Study excluded France

due to knowledge of the French Paradox is false and anachronistic. The concept of

the French Paradox did not exist until decades after SCS was launched. Further, WHO

and FAO data available around the time of the start of SCS gave no reason for

researchers to think that the French ate a richer diet or experienced significantly less heart

disease than other similar countries in Europe.6 Finally, France was not excluded from

SCS at all, but was invited- and French researchers declined to participate.8

37

The Seven Countries Study: Dietary Data in Greece

Critics of SCS often cite concerns with methodology in addition to country selection.

One criticism, predominantly featured in the book Big Fat Surprise, was that one of the

dietary surveys conducted in Crete took place during Lent.11 Because Lent requires

fasting among adherent Orthodox Greek Catholics, the author concluded that saturated fat

and animal food intake were significantly underestimated in SCS. How would this have

impacted the findings? Following this argument, it’s possible that the Greeks were eating

a moderate or even high saturated fat diet that went undetected by researchers. If true,

this would weaken the argument that saturated fat intake was significantly associated

with incidence of and mortality from heart disease, since both Greek cohorts had an

extremely low incidence. However, this critique overlooks several key points.

First, the SCS researchers were aware some dietary recalls occurred during Lent.3,12

Statistical comparisons were done and there were no differences in intake between

Lenten and non-Lenten sampling periods. Sampling during Lent, rather than being a

researcher oversight, was a purposeful choice. If diet was significantly different during

this time, it was important for researchers to capture those data accurately.3,8

Additionally, the findings of SCS in Greece were consistent with an earlier and

unaffiliated dietary intake study in Greece, suggesting that Keys et al. did collect accurate

data.3,13,14

Dietary differences during Lent

There were two cohorts examined in Greece: Crete, and Corfu. These cohorts were

unique due to the extremely low levels of heart disease these participants experienced,

and also their high fat intake (around 40% of calories in Crete).1,3 Dietary intake was

measured via in-depth, seven-day, precisely weighed food records: two in Corfu and

three in Crete. To validate the findings, a representative subsample of each cohort was

chosen and followed for a week. Throughout this week, all food eaten by participants was

38

weighed and measured by researchers, and proportional physical samples of all food were

taken, freeze-dried, and shipped back to the lab for chemical analysis. Then “food tables”

based on seven-day weighed food records and chemical analyses were created.12

When all the data for dietary intake in Greece were compared, researchers found little

variation in total intake between different dietary surveys.3 The February survey in Crete

and part of the March-April survey in Corfu were taken during Lent. In a 1968

monograph containing all of the dietary survey and chemical analysis methodologies,

researchers made a specific note: “The Greek Orthodox rules are much more strict than

those of the Roman Catholic Church and the ‘fasting’ period of eight weeks should,

theoretically, have a major impact on the total diet for the year. However… actual

practice is different from Church prescription.” Total caloric intake was “substantially

unaffected,” and the proportion of energy intake from the macronutrients was similarly

unaffected.12

From the same paper, researchers broke down food intake by percent of energy from

specific foods and percent energy from macronutrients. The argument that including

Lent in the survey would lower the percent of calories coming from saturated fat —

often simplified as animal fat in dietary tables — is effectively moot. As shown below

in Figure 4 from the 1968 monograph, “Dietary studies and epidemiology of heart

diseases,” the same animal fat intake was observed during Lent in Corfu and a slightly

higher intake of animal fat during Lent in Crete.12

Similarly, it can be seen below in Figure 5, a table from the same paper, that there

was little difference in total macronutrient intake between seasons.12 Below, researchers

aligned dietary intake measured by seven-day surveys next to corresponding values found

by chemical analysis. Generally, chemical analysis slightly underestimates fat intake. In

the monograph, den Hartog et al. theorize that this was likely due to fat from foods

adhering to the sides of collection tubes.12 (Readers with any experience using bomb

calorimetry for high fat foods like fast food or snack chips have likely experienced this

frustrating phenomenon.)

39

Figure4:From “Dietary studies and epidemiology of heart disease,” 1968, Stichting tot wetenschappelijke Voorlichting op Voedingsgebied. Permission to reproduce granted by the publisher.

Figure5:From “Dietary studies and epidemiology of heart disease,” 1968, Stichting tot wetenschappelijke Voorlichting op Voedingsgebied. Permission to reproduce granted by the publisher.

Far from overlooking the problems inherent with collecting dietary data during

a time of religious fasting, researchers actively sought to see a difference.3,12 In the

Greek Orthodox church, adherent practitioners can have between 180-200 annual days of

religious fasting, a sum that makes up at least half the year.64 It would be irresponsible

not to include days of ritual fasting in populations with high adherence since this would

40

affect the average dietary intake of people over a calendar year, though adherence does

not appear particularly strict in this case.

Averaged, researchers determined that men in both Corfu and Crete consumed 7%

and 8% of their daily calories from saturated fat respectively, with the other fats coming

from monounsaturated fat, and very small amounts from polyunsaturated fat.3 Total fat

intake in Corfu was estimated at 33% and in Crete at 40%, which is consistent with the

values represented in Figure 5.12

The Rockefeller Foundation Study

Some concerns have been expressed that the dietary survey data aren’t accurate for

other reasons, such as a small subgroup sample size. If this were the case, data reliability

could be examined by comparing dietary data collected by SCS with the summary of data

from any other dietary studies or food availability data at the same time. Inaccuracy could

be suspected if the SCS findings were to show values significantly different from those of

other dietary surveys.

In her paper on the history of the Mediterranean diet concept, Marion Nestle pointed

out that in 1948, three years past ravages of World War II, the Greek government was

interested in improving health and quality of life for citizens. It therefore enlisted the help

of scientists and funding from the Rockefeller Foundation to measure lifestyle factors.14

Among other measurements, this study also did seven-day weighed dietary surveys

among a sample of Greek citizens in Crete. The study, led by epidemiologist Leland

Allbaugh, compared the results of their dietary survey with FAO availability data and

energy available based on household food stores.13

Data were collected in 1948 and results were published in 1953. The results are

shown below (concurrent U.S. food balance is included for comparison).13,14

41

Figure6From "Mediterranean diets: historical and research overview," 1995, American Journal of Clinical Nutrition. Permission to reproduce original figure granted by the author.

Though the table is organized differently, it is clear that the results, published 15

years before the 1968 monograph, largely agree with the data of SCS. Oils and fats are

29% of total energy while animal foods are 4% and dairy is 3%.13 Animal foods plus

dairy make up 7% of the 1953 findings, while the combination of animal protein and

animal fats (which are comprised of roughly the same foods) made up 8.1%. If any major

difference appears, it is that the later dietary survey of SCS finds Greek men consuming

slightly more total calories.12 This makes sense, considering that the first survey was

conducted only three years after WWII and only one in every six families reported having

satisfactory diets.13,14 Participants generally stated that they would prefer to have more

food, particularly meat and other animal foods.

There is little evidence that Greek citizens were eating higher amounts of saturated fat

and animal foods that were not picked up in either dietary survey.

42

In conclusion, insinuations that Greek dietary data in SCS were inaccurate, negligent,

or unrepresentative are unfounded. Sampling during Lent was purposeful in order to

ensure accurate average intakes in Crete and Corfu. Further, the dietary findings showed

that Greek citizens did not significantly alter dietary intake during Lent. These dietary

data are consistent with earlier, high quality, independent dietary surveys undertaken in

Crete in the late 1940s.

43

Sugar vs. Saturated Fat in Heart Disease

Multiple sources have reported that SCS neglected deleterious effects of sugar on

health in favor of promoting a low-fat agenda.11,15 One accusation is that the regression

analyses used in SCS did not adjust for sugar as a possible confounder.65 Still another

stated that a later 1999 reanalysis of SCS data found that sugar was more highly

correlated with heart disease than saturated fat, proving that sugar, and not saturated fat,

was a culprit.11,15

Like the other arguments addressed in this paper, these criticisms do not withstand

scrutiny with attention to primary sources and historical documents. Sugar was adjusted

for in the multivariable analysis, as was discussed in the findings section above.3 The

1999 reanalysis did not upend the findings of the 1980 SCS publication; in fact, findings

remained consistent.

Adjustingforsugar

Summaries are quick to state that SCS did not consider sugar when statistical

analyses were performed searching for relationships between diet and heart disease. Had

these correlations been done, critics attest, it would be clear that sugar correlates as well

as or better than saturated fat with the incidence of heart disease.

The SCS investigators found and reported that sugar did correlate with heart disease.3

However, Keys et al. did not find that sugar was significantly related to heart disease

when the model was adjusted for saturated fat. This was consistent with experimental

findings at the time that failed to show a physiological mechanism directly connecting

sugar intake and heart disease.66 Ultimately, sugar received only a few paragraphs in the

1980 SCS publication not because there was something to hide, but because there was

nothing to show. Sugar was analyzed in the same way as saturated fat, and the findings

that resulted were the findings reported.3

44

Mechanistic involvement in heart disease

John Yudkin, a professor of nutrition in London, posited in the 1960s that heart

disease could be related to hyperinsulinemia caused by a high sugar diet.66 In his 1971

paper, “Sugar Intake and Coronary Heart Disease,” A.R.P. Walker explained the history

and state of nutrition science regarding sugar intake and heart disease. He included

descriptions of Yudkin’s human trials, which were published more than 12 years after the

start of SCS.66 During the four-week trials, participants consumed up to 40% of their

daily calories from sucrose for two weeks. Findings showed that the high sugar diet

caused no differences in glucose tolerance, serum cholesterol, or serum phospholipid

levels.66

However, Walker noted that one-third of subjects on the high sugar diet exhibited

hyperinsulinemia, and patients with previously established peripheral vascular disease on

the high sugar diets also experienced this outcome.66 This led to the suggestion that the

high sugar diet could cause adverse effects in people with a predisposition to develop

“sucrose-induced hyperinsulinism,” as Yudkin called it. These trials, while intriguing,

suffered from a confounding factor: The diets were not isocaloric. Those experiencing the

hyperinsulinism were gaining weight. Walker reported that in subsequent trials, Mann et

al. tested the results of reducing sugar intake in participants, and weight loss was a

confounding factor.66 As has been seen numerous times in human diet trials, it is difficult

to adjust intake of a single nutrient or macronutrient while maintaining isocaloric intake.

Further, the majority of case control and population observational studies that had

been completed by the mid-20th century found that those with coronary heart disease

weren’t consuming significantly more sugar than those without it.66 Dietary studies

swapping sucrose for other types of carbohydrate — namely starch — also found that

sugar had no overall relationship to health, although some studies found slightly raised

plasma triglycerides. In some case-control studies, the amount of sugar consumed by

those affected by heart disease was much less than the amount consumed by the control

45

groups without heart disease.66 This was difficult to square with a risk of heart disease

proportional to sugar intake.

In addition to Yudkin’s lack of statistical calculations — his association between

population data on sugar intake and heart disease relied on a scatter plot and no

calculated correlation coefficients — his population-wide observational studies suffered

from selection bias (a fault frequently attributed to Keys). In a critique by Ancel Keys, he

pointed out that countries with high sugar intakes, but low reported heart disease, like

Brazil, Colombia, Nicaragua, Uruguay, and Mauritius, were left out of Yudkin’s

analysis.38 It didn’t help that other scientists had found that sugar intake was statistically

correlated with a smoking habit, further muddying the waters in the crude ecologic

relationship between sucrose and heart disease.66

To much of the nutrition community at the time, links between sugar intake and heart

disease risk were simply unconvincing, especially when compared to the amount of data

linking saturated fat and heart disease.66

Figure7:From "Sugar intake and coronary heart disease," 1971, Atherosclerosis. This image has been reproduced from widely available reproductions accessible online. Permission to reproduce the original has been sought from the publisher, and a response is pending at this time.

46

A follow-up in 1999

A recent lay press article that dealt with the SCS — scintillatingly titled “The Sugar

Conspiracy” — tried to make the case that SCS was later discredited by one of its own

lead authors, Dr. Alessandro Menotti.15

“Years later,” the article said, “the Seven Countries study’s lead Italian researcher,

Alessandro Menotti, went back to the data, and found that the food that correlated most

closely with deaths from heart disease was not saturated fat, but sugar.”15

The correlations and conclusions mentioned above are not reported in the 1999

paper.16 When asked for comment, Dr. Menotti could not account for this conclusion: “I

never said that sugar was more correlated to coronary heart disease than other food

groups.”67

The 1999 follow-up on the dietary data was an attempt to look at the relationship

between specific foods and heart disease mortality. In earlier iterations of the study, each

food was broken down and analyzed according to its macronutrient components; this new

study took a “whole foods” approach.16

Unlike the conclusion reported in “The Sugar Conspiracy,” this analysis did not find

that sugar was more associated than saturated fat with heart disease mortality. Saturated

fat was not assessed individually, since it is a nutrient component and not a food.16

However, foods that are often considered proxies for saturated fat, like butter and other

animal fats, were assessed.

A significant positive association was found between sugar and death from coronary

heart disease (r=+0.60) that was consistent with earlier findings of the SCS.3,16 Foods that

contained high amounts of saturated fat, however, such as butter (r=+0.887), pastries (a

mix of sugar, carbohydrates, and fat (+0.752)), and all animal foods (r=+0.798), all had

stronger correlations with mortality from heart disease than did sugar.16

47

Accordingly, it is false to contend that SCS ignored or didn’t address the possible

relationship of sugar to heart disease. Today, there is more evidence that sugar and other

refined carbohydrates are not an advisable replacement for saturated fat sources in a

healthy diet.39,68–70 At the time of SCS, no experimentally determined mechanism existed

that linked sugar intake to heart disease. More importantly, sugar was not ignored.

Researchers assessed sugar intake, but no correlation between sugar and coronary heart

disease was found once saturated fat intake was controlled for in the analysis.3 In other

words, sugar intake in the SCS analysis correlated with coronary heart disease only to the

extent it correlated with intake of saturated fat.

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STRENGTHS AND LIMITATIONS OF THE SEVEN COUNTRIES STUDY

At the time of its inception, SCS was groundbreaking. Comparing incidence rates of

coronary heart disease across populations with vastly different traditional diets provided

information on risk that was not previously available.3 Though definitive causes of heart

disease could not be determined, it was clear that coronary heart disease was not simply a

matter of fate, but could be influenced by environment, lifestyle, and diet.

Prior to SCS, Keys and other researchers had noted seemingly different incidences of

chronic diseases, or diseases of aging, among populations they studied. Observational

studies of individual cultures limited researchers’ ability to compare diet, lifestyle, and

risk factors across cultures due to differences in study design, methodological quality,

and measured outcomes. Previously, national mortality and dietary statistics were highly

variable, which complicated attempts to compare diet and disease prevalence between

nations, such as in Keys’ 1953 paper and Yerushalmy and Hilleboe’s subsequent

response.6,7,47,55 SCS was able to bridge the gap by deliberately choosing vastly different

cohorts and comparing each with strictly standardized measures.

The development of these methods, including the Minnesota Code, which

standardized methods for measuring incidence of heart disease and confirming heart

disease mortality, represented a major breakthrough in epidemiology.21 Dietary records

were equally impressive and much more thorough than many recall tools used today, and

the chemical characterization of nutrient intake for the regions was unique.3,12

But like all scientific studies, especially groundbreaking ones, the study had

limitations, which were largely acknowledged and dealt with in SCS publications.

SCS was unable in its earlier follow-up years to detect any significant excess risk for

coronary heart disease or mortality associated with overweight or obesity.3 In fact, the

1980 study report for the 10-year coronary rates found that BMI was inversely correlated

49

with death rate in all cohorts. At the time, most participants were at least moderately

active, healthy men in their 40s and 50s, and the overall prevalence of obesity was low

compared to today’s levels.3 It is possible that SCS suffered from the same issue here that

occurred with smoking — there was not enough variation in individual or population

rates to reveal a meaningful correlation. It is consistent with modern research to find an

increased risk of death at weights below a BMI of 18, which was common in this study.

However, the average BMI in most countries hovered around 25, without extreme

variation within or among regions — meaning that most people were around normal

weight or slightly overweight.3 This would prevent SCS from finding many effects of

obesity or overweight.

Secondly, due to the lack of physiological evidence or plausible mechanism

connecting sucrose and atherosclerosis, refined sugar and carbohydrates were not given

prime attention. Modern epidemiological studies modeling the effects of swapping

saturated fat for refined carbohydrates and sugar suggest that there is no change in

risk when one is substituted for the other.71 In other words, the models suggest that

butter should not be swapped for sugar, or vice versa, to avoid excess heart disease risk.

Numerous studies observe that sources of polyunsaturated fats and whole grain or

unrefined carbohydrate products are superior.39,40 It is possible that this relationship was

not seen in SCS because sugar and saturated fat intake were highly correlated.3 Even so,

saturated fat was independently associated with heart disease rates, while sugar was not.

The SCS team was unable to take all of the measurements they wanted due to

practical constraints. For example, they initially were interested in getting glucose

tolerance tests and fractionated lipoprotein cholesterol, but were limited by the difficulty

of collecting these measures, shipping them to the central laboratory, and the associated

expense. Glucose tolerance would have put a major time burden on the participants

coming in and may have hurt participation rates. Additionally, lack of funds for incidence

studies in the U.S. cohort after the five-year mark meant that researchers could assess

outcomes only in coronary heart disease mortality in American men during the later years

of the study.3

50

The ecological design of SCS imposed important limitations, probably most

importantly difficulty in controlling for confounding. Because the primary outcomes

compared cohorts rather than individual participants’ values, correlations were drawn

using only 16 data points; the cohort means for measurements taken. This limited how

much could be inferred from more complex statistics employed in the study, like the

multivariable regression, because findings are limited by a modest sample size and

degrees of freedom. Additionally, sites were non-random and not meant to be

representative samples of each country, but purposefully varied in diet.18 This allowed

Keys et al. to see stark contrasts between diet, lifestyle, and disease outcomes but made

them less able to infer that these same variations in risk would carry over to populations

outside of the study samples.3

Though the 1980 publication gave little attention to foods, including sugar, BMI, or

smoking, in relation to total mortality, these are all limitations caused by lack of

statistical power or logistical challenges. Even with perfect data collection and analysis,

SCS can only report the comparative risks related to diet and heart disease within the

specific populations it studied.3 The diets of all cohorts in 1959-1964, when SCS dietary

data collection took place, were dissimilar to diets we think of as the “Standard American

Diet” today. Populations were not eating the high calorie, highly processed foods now so

common in diets across the globe, so it is sensible to be cautious when extrapolating the

findings of this single study.

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CONCLUSIONS

SCS provided invaluable information about the connections between diet and

coronary heart disease, in addition to developing important tools for standardizing

nutrition and diet research. Monographs published with five and 10-year follow-up data

showed that coronary heart disease and mortality were significantly associated with diets

higher in saturated fat.2,3 Follow-up data from 15 years of tracking all-cause and coronary

heart disease mortality found that diets high in saturated fats were associated with

increased risk for dying of heart disease, consistent with earlier findings.4 Allegations that

SCS was deliberately designed in order to find specific, preconceived outcomes are

decisively without merit.

Like all scientific studies, SCS had limitations, largely due to its ecological design,

and should be interpreted in the context of other evidence. Other concurrent, carefully

conducted studies, including the Framingham Heart Study, reached similar conclusions

for the associations between blood cholesterol levels and coronary heart disease risk.24

These other studies then inspired a series of randomized controlled dietary trials testing

the effects of fat substitution on heart disease risk that had findings consistent with those

of the large-scale epidemiological nutrition studies.72 The aggregation of this evidence,

together with other scientific findings and many other influences, contributed to the

original 1980 dietary guidelines and still influences the guidelines today.73 All sets of

dietary guidelines have advocated for limited intake of saturated fats as well as

sugars.73,74 Of note, Ancel Keys was only briefly interested in total fat intake as an

important variable; his own data quickly dissuaded him from that focus, and shifted his

attention to saturated fat.

Misleading, or negligent criticism of seminal research in nutrition science undermines

the credibility of all science and the process by which understanding advances. Detractors

invite false equivalence by allowing studies of smaller impact and dubious quality to be

compared against large-scale, scrupulously conducted research. Current examples of the

insidious dangers of such a process include climate change denial, and false allegations

52

about the effects of childhood immunization. As a result of the latter, the United States

and other developed nations have seen an increase in vaccine preventable diseases and

subsequently an increase in deaths from these diseases.75 The public health impact of

false or misleading narratives about nutrition research is potentially much larger even

than that of vaccines.

Heart disease is the number one killer in America and worldwide.76,77 The thesis of

the many articles and books disparaging SCS and the life work of Ancel Keys is that

serum cholesterol and saturated fat foods are not related to heart disease. Heart disease

has decreased significantly since the 1950s, however, and despite the increase in obesity

during that same time period. These declines are thought to be due to public health

interventions addressing lifestyle practices, including a significant shift from dietary

sources of saturated fats to sources of unsaturated fats, as well as medical advances.76 In

North Karelia, Finland, where the SCS findings and the work of Ancel Keys were used

directly and with fidelity as the basis for intervention at the community level, heart

disease rates plummeted over 80% in the decades that followed, and average life

expectancy increased by a full ten years.78–80 There, too, along with other changes,

calories from dietary sources of saturated fat, especially dairy fat, were replaced largely

with dietary sources of unsaturated fats.

Recently, the decline in coronary heart disease incidence in the United States has

slowed.76 Rates of heart disease in North Karelia, Finland, have risen slightly for the first

time in half a century, in apparent tandem, whether coincidentally or causally, with

popular messaging about the advantages of eating more “meat, butter, and cheese.”81

In the preface for the 2002 monograph Prevention of coronary heart disease: Diet,

lifestyle and risk factors in the Seven Countries Study, Ancel Keys summarizes:

“The results of the Seven Countries Study… should be viewed in this broader context

of the role of the diet, lifestyle and risk factors in relation to all causes of deaths and to

longevity. This should be the ultimate goal of epidemiologic research.”18

53

Like all studies, SCS should be analyzed and utilized in context, with strengths and

weaknesses acknowledged. By deliberately or carelessly misrepresenting historical

events, distorting scientific findings, and misstating researcher intent, modern critics of

the SCS routinely impede, rather than advance, understanding in nutritional

epidemiology.

54

EDITORIAL EPILOGUE: The Legacy of Ancel Keys and the SCS By David Katz, MD, MPH

This White Paper, relying preferentially and to the extent possible on primary sources

and first-hand accounts, decisively falsifies the popular disparagements directed at Ancel

Keys and the Seven Countries Study. The Seven Countries Study included exactly seven,

and neither six nor 22, countries. Keys and colleagues did not cherry-pick the

participating countries; they did not exclude France; they did not present or graph their

data selectively; they did include dietary intake surveys in Greece during Lent

intentionally, for reasons clearly articulated at the time, and with proof that this did not

introduce any distortions; and they did analyze sugar in all the same ways they analyzed

saturated fat, and reported just what they found.

The popularization of flagrant falsehoods about all of the above is possible for several

reasons: the primary source materials are now decades old, and few have or bother to

seek recourse to them; the Internet lacks reliable editorial filtering or fact-checking

mechanisms, so idle opinion passes routinely for expertise; repetition in cyberspace and

social media is nearly effortless, and oft-repeated falsehoods can “drown out” evidence

and truth with sheer volume; messages are invariably distorted in sequential transmission,

as in the party game, “telephone;” and, conveniently for his detractors, Keys is

unavailable to defend himself posthumously against even the most readily refuted

falsehoods.82,83

This much the paper establishes. It stops there, however, because that was the charge

to which it was responsive: a reality check about history, and a response to revisionist

alternatives. But what about the legacy of Keys and the SCS and its reverberations into

modern public health?

Keys has been routinely implicated in the low-fat dietary digression that brought us

such low-fat junk foods as Snackwell cookies; that increased our intake of refined grains,

added sugar, and total calories; and that failed to advance leading public health objectives

55

related to diet.84,85 This charge, too, is clearly false. Primary sources, and first-hand

accounts by investigators both indicate that Keys observed an association between (total)

dietary fat intake and heart disease in his early data. According to colleagues, however,

Keys routinely did with such observations what good scientists should do: turned them

into testable hypotheses, not immutable convictions.49 He proceeded to test this

hypothesis himself, and concluded long before the dawn of the “low fat” diet era that

total dietary fat quantity was unimportant, while the sources and quality of fat were

important. Over the course of his career, he advocated for restricting saturated (and,

albeit with lesser attention, trans fat), fat by shifting from animal-food-centric to plant-

food-centric diets; and lent his strongest support to the natively high-unsaturated-fat

Mediterranean diet. Keys published a Mediterranean diet cookbook in 1959.86

Misadventures in low-fat eating, to say nothing of low-fat junk foods, cannot

legitimately be attributed to any position espoused by Keys over the course of his career.

That there was a foray into misguided applications of a low-fat dietary approach with

ramifications still relevant today is undeniable. Reasons for it are complex, contentious,

and beyond the scope of this paper- and perhaps fodder for another. But it is clear that

responsibility cannot legitimately be assigned either to Keys, or the Seven Countries

Study.

There are published claims that Keys was unduly confident about specific

associations, such as that between saturated fat and heart disease, given the ecological

nature of the SCS. However, the written record and other first-hand accounts indicate

that (a) Keys almost without fail carefully avoided any temptation to overstate the

significance of his findings in published work; and (b) he based his

impressions/conclusions on the overall mass of evidence, not just the SCS. Importantly,

his views evolved over the course of his career in accord with the evolving evidence base.

Among the currently popular narratives is that sugar is the culprit saturated fat was

long thought to be; that the contributions of sugar to cardiovascular disease were willfully

concealed by vested interests; and that Keys and the SCS were complicit in this. The

56

reality here is that efforts to veil the harms of sugar obviously failed, since the Dietary

Guidelines for Americans have emphasized limiting sugar intake since the first in

1980.73,87 Keys, and the SCS, gave sugar its day in court, and reported just what they

found. Studies conducted by Keys and his SCS colleagues did reveal an association

between sugar intake and cardiovascular disease, albeit a weaker one than for dietary

sources of saturated fat. Nothing in this body of work ever encouraged or justified the

substitution of added sugar for saturated fat, and Keys was never an advocate for any

such thing. There is more than one way to eat badly, and if the American public has been

committed to exploring them sequentially, blame for it cannot be laid at the door- or now

the grave- of Ancel Keys.

Viewing serum lipids as a key mediator of the effects of diet on the cardiovascular

system, Keys was initially interested in total cholesterol, and then both LDL and HDL,

but settled on the observation that LDL was of singular importance. His view on this

matter seems to have anticipated by some decades the very conclusion now favored by a

consensus of experts, and the shifting weight of relevant evidence.88,89

The principal conclusion of the SCS germane to public health practice was that heart

disease was preventable with lifestyle and not an inevitable consequence of aging (a new

concept at the time), and that dietary intake of saturated fat from its prevailing food

sources (meat, processed meat, and dairy products then; with fast food and various

processed foods appended now) should be reduced and replaced by whole foods, mostly

plants, and the unsaturated oils derived from olives in particular, but also nuts, seeds,

avocados, fish, and seafood- to lower cardiovascular disease risk. That conclusion has

since been reached by diverse experts in diverse settings on the basis of diverse research

all independent of the SCS.40,71,74,90–104

That conclusion was converted into practice in North Karelia, Finland, with fidelity to

the findings of the SCS rather than the distortions that produced low-fat junk food in the

United States. The result was a reduction in incident coronary disease of more than 80%,

and an average addition to life expectancy of more than ten years.80 While these results

57

were not solely attributable to a shift from animal foods to plant foods, with an attendant

drop in saturated fat intake, that was a prominent component of the campaign.78

Keys may have been somewhat dismissive of trans fat, but mostly because it occupied

a very tiny niche in the American diet at the time of his initial work. He may have been

somewhat dismissive of the importance of obesity to cardiovascular outcomes, but mostly

because weight varied rather little among the workers enrolled in the SCS. He may have

been somewhat inattentive to the adversities of smoking, again for lack of variation in the

exposure among his study participants. Overall, though, based on both data he generated,

and data generated by others, Keys evolved positions remarkably consistent with those

reached independently on the basis of the most current evidence on: overall dietary

pattern; total dietary fat; saturated fat; unsaturated fat; sugar; LDL; and dietary

cholesterol, which Keys recognized as relatively unimportant to serum cholesterol levels.

None of the first-hand accounts of Keys included the claim that he never made

mistakes, or the recommendation that he be canonized. All concurred, however, that he

was a diligent, meticulous, groundbreaking scientist who followed the data where they

led. On the basis of data, and perhaps good intuition as well, Keys anticipated the

evidence and consensus-based positions of public health nutrition in 2017 with

extraordinary accuracy and consistency. When public health nutrition in the modern era

has gone awry, it has never done so in accord with the findings and positions of Ancel

Keys. It has done so because such findings have been distorted; such positions

misrepresented; and the important lessons of this period of nutrition history, and the

singular contributions of Ancel Keys, forgotten and replaced with false narratives.

-David L. Katz, MD, MPH

Founder & President, The True Health Initiative

Immediate Past President, The American College of Lifestyle Medicine

Director, Yale University Prevention Research Center

Griffin Hospital

Derby, CT

58

REFERENCES 1. Keys,A.,Aravanis,C.,Blackburn,H.W.,vanBuchem,S.P.,Buzina,R.,

Djordjevic,B.S.,Dontas,A.S.,Fidanza,F.,Karvonen,M.J.,Kimura,N.,Lekos,D.,Monti,M.,Puddu,V.TaylorHL.Epidemiologicalstudiesrelatedtocoronaryheartdisease:Characteristicsofmenaged40-59insevencountries.ActaMedScand.1966;460:1-392.

2. KeysA.Coronaryheartdiseaseinsevencountries.Circulation.1970;41(S1):118-139.

3. Keys,A,Aravanis,C.,Blackburn,H.,Buzina,R.,Djordjevic,B.S.,Dontas,A.S.,Fidanza,F.,Karvonen,M.J.,Kimura,N.,Menotti,A.,Mohacek,I.,Nedeljkovic,S.,Pussu,V.,Punsar,S.,Taylor,H.L.,VanBuchemFSP.SevenCountries:AMultivariateAnalysisofDeathandCoronaryHeartDisease.Cambridge,MA:HarvardUniversityPress;1980.

4. KeysA,MenottiA,KarvonenMJ,etal.Thedietand15-yeardeathrateinthesevencountriesstudy.AmJEpidemiol.1986;124(6):903-915.

5. FraminghamHeartStudy.ResearchMilestones.https://www.framinghamheartstudy.org/about-fhs/research-milestones.php.Published2017.

6. YerushalmyJ,HilleboeH.FatintheDietandMortalityfromHeartDisease:AMethodologicNote.NYStateJMed.1957:2343-2354.

7. KeysA.Epidemiologicaspectsofcoronaryarterydisease.JChronicDis.1957;6(5):552-559.http://www.ncbi.nlm.nih.gov/pubmed/13475453.

8. BlackburnH.personalcommunication.2017.9. BlackburnH,KromhoutD,AM.TheSevenCountriesStudy:Ascientific

adventureincardiovasculardiseaseepidemiology.1994:15-37-159.10. DeLeirisJ,BoucherF,DucimetiereP,HoldsworthM.TheFrenchParadox :

FactorFiction ?ExpertAnswerstoThreeKeyQuestions.DialoguesCardiovascMed.2008;13(3).

11. TeicholzN.TheBigFatSurprise:WhyButter,Meat,andCheeseBelonginaHealthyDiet.NewYork:Simon&Schuster;2014.

12. denHartogC,BuzinaK,FidanzaF,KeysA,RoineP.DietaryStudiesandEpidemiologyofHeartDiseases.TheHague;1968.http://edepot.wur.nl/380320.

13. AllbaughLG.Crete:ACaseStudyofanUnderdevelopedArea.PrincetonUniversityPress;1953.

14. NestleM.Mediterraneandiets:historicalandresearchoverview.AmJClinNutr.1995;61(suppl):1313S-1320S.

15. LeslieI.Thesugarconspiracy.Guard.2016.https://www.theguardian.com/society/2016/apr/07/the-sugar-conspiracy-robert-lustig-john-yudkin.

16. Menottia,KromhoutD,BlackburnH,FidanzaF,BuzinaR,Nissinena.Foodintakepatternsand25-yearmortalityfromcoronaryheartdisease:cross-culturalcorrelationsintheSevenCountriesStudy.TheSevenCountriesStudyResearchGroup.EurJEpidemiol.1999;15(6):507-515.

59

doi:10.1023/A:1007529206050.17. KeysA,MenottiA,AravanisC,etal.TheSevenCountriesStudy:2,289Deaths

in15Years.1984;154:141-154.18. KromhoutD,MenottiA,BlackburnH.PreventionofCoronaryHeartDisease:

Diet,LifestyleandRiskFactorsintheSevenCountriesStudy.NewYork:KluwerAcademicPublishers;2002.doi:10.1007/978-1-4615-1117-5.

19. LozanoR,MurrayC,LopezA.Miscodingandmisclassificationofischaemicheartdiseasemortality.WorldHealth.2001;12(12):1-19.

20. RoseG,BlackburnH.CardiovascularSurveyMethods.WorldHealthOrganizationTechnicalReportSeriesNo.56.Geneva:WorldHealthOrganization;1968.

21. BlackburnH.Electrocardiographicclassifictionforpopulationcomparisons:TheMinnesotacode.JElectrocardiol.1969;2(1):5-9.doi:https://doi.org/10.1016/S0022-0736(69)80044-0.

22. BlackburnH,KeysA,SimonsonE,RautaharjuP,PuntsarS.TheElectrocardiograminPopulationStudiesAClassificationSystem.Circulation.1960;XXI:1160-1175.doi:https://doi.org/10.1161/01.CIR.21.6.1160.

23. KromhoutD,KeysA,AravanisC,etal.Foodconsumptionpatternsinthe1960sinsevencountries.AmJClinNutr.1989;49(5):889-894.http://ajcn.nutrition.org/content/49/5/889.abstract.

24. MahmoodaSS,LevyD,VasanRS,WangTJ.TheFraminghamHeartStudyandtheepidemiologyofcardiovasculardiseases:Ahistoricalperspective.Lancet.2014;383(9921):1933-1945.doi:10.1016/S0140-6736(13)61752-3.The.

25. TsaoCW,VasanRS.CohortProfile:TheFraminghamHeartStudy(FHS):Overviewofmilestonesincardiovascularepidemiology.IntJEpidemiol.2015;44(6):1800-1813.doi:10.1093/ije/dyv337.

26. KeysA,TaylorH,BlackburnH,BrozekJ,AndersonJ,SimonsonE.CoronaryHeartDiseaseamongMinnesotaBusinessandProfessionalMenFollowedFifteenYears.Circulation.1963;28(3):381-395.doi:10.1161/01.CIR.28.3.381.

27. BorhaniNO,HechterHH,BreslowL.ReportofaTen-YearFollow-UpStudyoftheSanFranciscoLongshoremen:MortalityFromCoronaryHeartDiseaseandFromAllCauses.JChronicDis.1963;16:1251-1266.http://www.ncbi.nlm.nih.gov/pubmed/14104335.

28. BeatonGH,MilnerJ,CoreyP,McGuireV,Al.E.Sourcesofvariancein24-hourdietaryrecalldata:Implicationsfornutritionstudydesignandinterpretation.AmJClinNutr.1979;32(12):3546-3559.

29. JacobsDR,AndersonJT,BlackburnH.Dietandserumcholesterol:Dozerocorrelationsnegatetherelationship?AmJEpidemiol.1979;110(1):77-87.doi:10.1093/oxfordjournals.aje.a112791.

30. LiuK,StamlerJ,DyerA,McKeeverJ,McKeeverP.Statisticalmethodstoassessandminimizetheroleofintra-individualvariabilityinobscuringtherelationshipbetweendietarylipidsandserumcholesterol.JChronicDis.1977;31(6-7):399-418.doi:https://doi.org/10.1016/0021-9681(78)90004-8.

31. KaplanH,ThompsonRC,TrumbleBC,etal.CoronaryatherosclerosisinindigenousSouthAmericanTsimane:Across-sectionalcohortstudy.TheLancet.2017.

60

32. A.MJ,MasesaZ,StrømmeSB,AlE.DailyenergyexpenditureandcardiovascularriskinruralandurbanBantuTanzanians.BrJSportsMed.2010;44:121-126.

33. OrlichMJ,FraserGE.VegetariandietsintheAdventistHealthStudy2 :areviewofinitial.AmJClinNutr.2014;100:2-7.doi:10.3945/ajcn.113.071233.Am.

34. BlackburnH.20th-Century“MedicalMarcoPolos”intheOriginsofPreventiveCardiologyandCardiovascularDiseaseEpidemiology.AmJCardiol.2012;109(5):756-767.doi:10.1016/j.amjcard.2011.10.038.

35. KromhoutD.PersonalCommunication.2017.36. BlackburnH.PersonalCommunications.2017.37. KatzD,WildD,ElmoreJ,LucanS.Jekel’sEpidemiology,Biostatistics,Preventive

Medicine,andPublicHealth.4thed.Saunders;2013.38. KeysA.Sucroseinthedietandcoronaryheartdisease.Atherosclerosis.

1971;14(2):193-202.doi:10.1016/0021-9150(71)90049-9.39. HuF,WillettW.Optimaldietsforpreventionofcoronaryheartdisease.JAm

MedAssoc.2002;288(20):2569-2578.http://dx.doi.org/10.1001/jama.288.20.2569.

40. KatzDL,MellerS.CanWeSayWhatDietIsBestforHealth?AnnuRevPublicHealth.2014;35(1):83-103.doi:10.1146/annurev-publhealth-032013-182351.

41. KeysA,AndersonJT,GrandeF.Predictionofserum-cholesterolresponsesofmantochangesinfatsinthediet.Lancet.1957;273(7003):959-966.

42. GrandeF,AndersonJT,KeysA.Theinfluenceofchainlengthofthesaturatedfattyacidsontheireffectonserumcholesterolconcentrationinman.JNutr.1961;74:420-428.

43. BorénJ,WilliamsKJ.Thecentralroleofarterialretentionofcholesterol-richapolipoprotein-B-containinglipoproteinsinthepathogenesisofatherosclerosis.CurrOpinLipidol.2016;27(5):473-483.doi:10.1097/MOL.0000000000000330.

44. @ziobrando.Thebullshit[asymmetry].2013.https://twitter.com/ziobrando/status/289635060758507521.

45. SevenCountriesStudy.Wikipedia.46. KeysA.theDiet/HeartControversy.Lancet.1979;314(8147):844-845.

doi:10.1016/S0140-6736(79)90331-3.47. KeysA.Atherosclerosis:aprobleminnewerpublichealth.JMtSinaiHospNY.

1953;20(2):118-139.48. EstruchR,RosE,Salas-SalvadóJ,etal.PrimaryPreventionofCardiovascular

DiseasewithaMediterraneanDiet.NEnglJMed.2013;368:1279-1290.doi:10.1056/NEJMoa1200303.

49. KromhoutD,KatanMB,BlackburnH,MenottiA,JacobsDR,WillettWC.PersonalCommunication.2017.

50. JacobsDR.PersonalCommunication.2017.51. KesternichI,SiflingerB,SmithJP,WinterJK.TheEffectsofWorldWarIIon

EconomicandHealthOutcomesacrossEurope.RevEconStat.2014;96(1):103-118.doi:10.1162/REST_a_00353.

61

52. LoweK.SavageContinent:EuropeintheAftermathofWorldWarII.NewYork:St.Martin’sPress;2012.

53. CollinghamL.TheTasteofWar:WorldWarIIandtheBattleforFood.NewYork:ThePenguinPress;2012.

54. BlackburnH.FamousPolemicsonDiet-HeartTheory.http://www.epi.umn.edu/cvdepi/essay/famous-polemics-on-diet-heart-theory/%0D%0D.

55. HilleboeH.SomeEpidemiologicAspectsofCoronaryArteryDisease.JChronicDis.1957;6(3):210-228.doi:https://doi.org/10.1016/0021-9681(57)90003-6.

56. Bradford-HillA.TheEnviromentandDisease:AssociationorCausation?ProcRSocMed.1965;58:295-300.doi:DOI:10.1016/j.tourman.2009.12.005.

57. StanhopeB-J,BurdetteWJ,CochranWG,etal.ReportoftheAdvisoryCommitteetotheSurgeonGeneralofthePublicHealthService.…,EducWelfare,PublicHealServ….1964:1-386.http://profiles.nlm.nih.gov/NN/B/B/M/Q/_/nnbbmq.ocr.

58. BlackburnH,LabartheD.Storiesfromtheevolutionofguidelinesforcausalinferenceinepidemiologicassociations:1953-1965.AmJEpidemiol.2012;176(12):1071-1077.doi:10.1093/aje/kws374.

59. DavisM.HowWorldWarIIshapedmodernFrance.Euronews.May2015.http://www.euronews.com/2015/05/05/how-world-war-ii-shaped-modern-france.

60. KeysA.Wine,garlic,andCHDinSevenCountries.Lancet.1980;315(8160):145-146.doi:https://doi.org/10.1016/S0140-6736(80)90620-0.

61. Tunstall-PedoeH,KuulasmaaK,MarkkuM,TolonenH,RuokokoskiE,AmouyelP.Contributionoftrendsinsurvivalandcoronary-eventratestochangesincoronaryheartdiseasemortality-10-yearresultsfrom37WHOMONICAProjectpopulations.Lancet.1999;353(9164):1547-1557.doi:https://doi.org/10.1016/S0140-6736(99)04021-0.

62. DucimetiereP,RichardJL,CambienF,RakotovaoR,ClaudeJR.Coronaryheartdiseaseinmiddle-agedFrenchmen:ComparisonsbetweenParisProspectiveStudy,SevenCountriesStudy,andPoolingProject.1980;315(8182):1346-1350.doi:https://doi.org/10.1016/S0140-6736(80)91796-1.

63. Tunstall-pedoeH.Autrespays,Autresmoeurs.TheoriesonwhytheFrenchhavelessheartdiseasethantheBritishReinvestigateandchangethetreatment.BrMedJ.1988;297(6683):1559-1560.

64. SarriKO,LinardakisMK,BervanakiFN,TzanakisNE,KafatosAG.GreekOrthodoxfastingrituals:ahiddencharacteristicoftheMediterraneandietofCrete.BrJNutr.2004;92(2):277.doi:10.1079/BJN20041197.

65. LustigR.FatChance:BeatingtheOddsAgainstSugar,ProcessedFood,Obesity,andDisease.NewYork:Penguin;2013.

66. WalkerARP.Sugarintakeandcoronaryheartdisease.Atherosclerosis.1971;14:137-152.internet:http://edepot.wur.nl/380320.

67. MenottiA.Personalcommunication.2017.68. MensinkRP,ZockPL,KesterADM,KatanMB.Effectsofdietaryfattyacidsand

62

carbohydratesonserumtotaltoHDLcholesterolandserumlipidsandapolipoproteins:ameta-analysisof60controlledtrials.2003;77:1146-1155.

69. Siri-tarinoPW,SunQ,HuFB,KraussRM.Saturatedfat,carbohydrate,andcardiovasculardisease.AmJClinincalNutr.2010;(5):502-509.doi:10.3945/ajcn.2008.26285.INTRODUCTION.

70. WillettWC.Dietaryfatsandcoronaryheartdisease.JInternMed.2012;272(1):13-24.doi:10.1111/j.1365-2796.2012.02553.x.

71. LiY,HrubyA,BernsteinAM,etal.SaturatedFatasComparedWithUnsaturatedFatsandSourcesofCarbohydratesinRelationtoRiskofCoronaryHeartDisease:AProspectiveCohortStudy.JAmCollCardiol.2016;66(14):1538-1548.doi:10.1016/j.jacc.2015.07.055.Saturated.

72. SacksFM,LichtensteinAH,WuJHY,etal.Dietaryfatsandcardiovasculardisease:ApresidentialadvisoryfromtheAmericanHeartAssociation.Circulation.2017;135.doi:10.1161/CIR.0000000000000510.

73. U.S.DepartmentofHealthandHumanServices,U.S.DepartmentofAgriculture.NutritionandYourHealth:DietaryGuidelinesforAmericans,1980.1980.https://health.gov/dietaryguidelines/1980.asp.

74. DietaryGuidelinesAdvisoryCommittee.ScientificReportofthe2015DietaryGuidelinesAdvisoryCommittee.;2015.

75. PhadkeVK,BednarczykRA,SalmonDA,OmerSB,HealthG.Associationbetweenvaccinerefusalandvaccine-preventablediseasesintheUnitedStates:Areviewofmeaslesandpertussis.JAmMedAssoc.2016;315(11):1149-1158.doi:10.1001/jama.2016.1353.Association.

76. SidneyS,QuesenberryCP,JaffeMG,etal.RecentTrendsinCardiovascularMortalityintheUnitedStatesandPublicHealthGoals.JAMACardiol.2016;1(5):594.doi:10.1001/jamacardio.2016.1326.

77. BarqueraS,Pedroza-TobiasA,Hernández-BarreraL,Bibbins-DomingoK,LozanoR,MoranA.Globaloverviewoftheepidemiologyofatheroscleroticcardiovasculardisease.ArchMedRes.2015;46(5):328-338.doi:10.1016/j.arcmed.2015.06.006.

78. PuskaP.Successfulpreventionofnon-communicablediseases:25yearexperienceswithNorthKareliaProjectinFinland.PublicHealMed.2002;4(1):5-7.doi:10.1136/bmjopen-2014-006070.

79. PietinenP,NissinenA,VartiainenE,etal.DietarychangesintheNorthKareliaProject(1972-1982).PrevMed(Baltim).1988;17(2):183-193.doi:10.1016/0091-7435(88)90062-X.

80. JousilahtiP,LaatikainenT,SalomaaV,PietilaA,VartiainenE,PuskaP.40-YearCHDmortalitytrendsandtheroleofriskfactorsinmortalitydecline:TheNorthKareliaProjectexperience.GlobHeart.2016;11(2):207-212.https://www.ncbi.nlm.nih.gov/pubmed/27242088.

81. VartiainenE.PersonalCommunication.2017.82. NicholsT.TheDeathofExpertise.Fed.January2014.

http://thefederalist.com/2014/01/17/the-death-of-expertise/.83. KatzD.OpinionStew.HuffingtPost.April2013.

http://www.huffingtonpost.com/david-katz-md/nutrition-advice_b_3061646.html.

63

84. NelsonL.WatchtherapidevolutionoftheAmericandietover40years,inoneGIF.May2016.https://www.vox.com/2016/5/18/11704458/american-diet-changes.

85. MossM.TheExtraordinaryScienceofAddictiveJunkFood.NYTimesMag.2017:1-25.http://www.nytimes.com/2013/02/24/magazine/the-extraordinary-science-of-junk-food.html.

86. KeysA,KeysM.EatWellandStayWell.GarcenCity:Doubleday&Company,Inc;1959.

87. KatzDL.SugarcoatingDietScience :SeekingSimpleTruth,PasttheFrosting.2017:1-3.https://www.linkedin.com/pulse/sugarcoating-diet-science-seeking-simple-truth-past-david?trk=mp-reader-card.

88. SilvermanM,FerenceB,ImK,etal.AssociationbetweenloweringLDL-Candcardiovascularriskreductionamongdifferenttherapeuticinterventions:Asystematicreviewandmeta-analysis.JAmMedAssoc.2016;312(12):1289-1297.doi:10.1001/jama.2016.13985.

89. Lloyd-JonesDM,MorrisPB,BallantyneCM,etal.2016ACCExpertConsensusDecisionPathwayontheRoleofNon-StatinTherapiesforLDL-CholesterolLoweringintheManagementofAtheroscleroticCardiovascularDiseaseRisk.JAmCollCardiol.2016;68(1):92-125.doi:10.1016/j.jacc.2016.03.519.

90. McGinnisJ,FoegeW.ActualcausesofdeathintheUnitedStates.JAmMedAssoc.1993;270(18):2207-2212.doi:10.1001/jama.1993.03510180077038.

91. KheraAV.,EmdinCA,DrakeI,etal.Geneticrisk,adherencetoahealthylifestyle,andcoronarydisease.NEnglJMed.2016;375(24):2349-2358.doi:10.1056/NEJMoa1605086.Genetic.

92. LeySH,HamdyO,MohanV,HuFB.PreventionandManagementofType2Diabetes:DietaryComponentsandNutritionalStrategies.Lancet.2014;383(9933):1999-2007.doi:10.1016/S0140-6736(14)60613-9.Prevention.

93. WangD,LiY,ChiuveS,etal.AssociationofSpecificDietaryFatswithTotalandCause-SpecificMortality.JAmMedAssoc.2016;176(8):1134-1145.https://www.ncbi.nlm.nih.gov/pubmed/27379574.

94. TrichopoulouA,BamiaC,TrichopoulosD.AnatomyofhealtheffectsofMediterraneandiet:GreekEPICprospectivecohortstudy.BrMedJ.2009;338(b2337).doi:10.1136/bmj.b2337.

95. SongM,FungT,HuF,etal.Associationofanimalandplantproteinintakewithall-causeandcause-specificmortality.JAmMedAssoc.2016;176(10):1453-1463.doi:10.1001/jamainternmed.2016.4182.

96. SpringmannM,GodfrayHCJ,RaynerM,ScarboroughP.Analysisandvaluationofthehealthandclimatechangecobenefitsofdietarychange.ProcNatlAcadSci.2016;113(15):1-6.doi:10.1073/pnas.1523119113.

97. FordE,BergmannM,KrögerJ,SchienkiewitzA,WeikertC,BoeingH.Healthylivingisthebestrevenge:findingsfromtheEuropeanProspectiveInvestigationIntoCancerandNutrition-Potsdamstudy.ArchInternMed.2009;169(15):1355-1362.doi:10.1001/archinternmed.2009.237.

98. EtemadiA,SinhaR,WardMH,etal.Mortalityfromdifferentcausesassociatedwithmeat,hemeiron,nitrates,andnitritesintheNIH-AARPDietandHealth

64

Study :populationbasedcohortstudy.BrMedJ.2017;357(j1957):1-11.doi:10.1136/bmj.j1957.

99. FreemanAM,MorrisPB,BarnardN,etal.Trendingcardiovascularnutritioncontroversies.JAmCollCardiol.2017;69(9):1172-1187.doi:10.1016/j.jacc.2016.10.086.

100. MichaR,PeñalvoJL,CudheaF,ImamuraF,RehmCD,MozaffarianD.Associationbetweendietaryfactorsandmortalityfromheartdisease,stroke,andtype2diabetesintheUnitedStates.JAmMedAssoc.2017;317(9):912-924.doi:10.1001/jama.2017.0947.

101. Sotos-PrietoM,BhupathirajuSN,MatteiJ,etal.Associationofchangesindietqualitywithtotalandcause-specificmortality.NEnglJMed.2017;377:143-153.doi:10.1056/NEJMoa1613502.

102. BernsteinAM,SunQ,HuFB,StampferM,MansonJE,WillettWC.MajorDietaryProteinSourcesandtheRiskofCoronaryHeartDiseaseinWomen.Circulation.2010;122(9):876-883.doi:10.1161/CIRCULATIONAHA.109.915165.Major.

103. DiabetesPreventionProgramResearchGroup.Reductionintheincidenceoftype2diabeteswithlifestyleinterventionormetformin.NEnglJMed.2002;346(6):393-403.doi:10.1056/NEJMoa012512.

104. LorgerilMDe,SalenP,MartinJ-L,MonjaudI,DelayeJ,MamelleN.MediterraneanDiet,TraditionalRiskFactors,andtheRateofCardiovascularComplicationsAfterFinalReportoftheLyonDietHeartStudy.Circulation.1999;99(6):779-785.doi:https://doi.org/10.1161/01.CIR.99.6.779.

FormoreinformationabouttheSevenCountriesStudy,visit:http://www.sevencountriesstudy.com/